IMMUNE ESCAPE MECHANISMS IN LEISHMANIASIS

描述(由申请人提供)：感染原生动物寄生虫主要利什曼原虫在世界许多地区造成严重的发病率。大圆线虫感染小鼠模型被认为是研究体内Th1/Th2细胞因子极化反应的范例，其中IL-4驱动的Th2反应是大圆线虫感染易感性的决定因素。与这一成熟的模型相反，在缺乏IL-4受体阿尔法链(IL-4Rpha-/-)的遗传纯BALB/c小鼠中，感染主要乳杆菌亚株LV39会导致高度进展性疾病；与易感的BALB/c小鼠相似，而主要乳杆菌亚株IR173受到高度控制。这些结果表明，除IL-4外，其他因素也能够抑制IFNGamma激活的对细胞内主要寄生虫的杀伤。IL-10被认为是导致IL-4Ra-/-小鼠对主要左旋支原体Lv39易感性的因素。在用中和抗IL-10受体抗体治疗的IL-4Ra-/-小鼠和同时缺乏IL-4Ra和IL-10的BALB/c小鼠中，主要Lv39感染的疾病被逆转为治愈表型。这项建议利用主要乳杆菌LV39和IR173感染的不同结果来评估细胞因子调节、分泌IL-10的Treg细胞的作用、巨噬细胞和树突状细胞在引导T细胞对主要乳杆菌感染的免疫反应中的作用以及主要乳杆菌疫苗的保护作用和机制。这些研究的长期目标是确定参与L.主要免疫逃逸机制的细胞过程和抗原，这些机制在缺乏IL-4/IL-13信号的情况下得到充分揭示。这些研究对开发针对利什曼原虫感染的治疗方法和疫苗以及体内调节Th1/Th2细胞因子发展的机制具有重要意义。

DESCRIPTION (provided by the applicant): Infection with the protozoan parasite Leishmania major causes significant morbidity in many parts of the world. The mouse model of L. major infection has been considered the paradigm to study polarized Th1/Th2 cytokine responses in vivo, with IL-4-driven Th2 responses as a determinant of susceptibility to L. major infection. Contrary to this well-established model, in genetically pure BALB/c mice deficient for IL-4 receptor alpha chain (IL-4Ralpha-/-), infection with L. major sub-strain LV39 causes highly progressive disease; similar to susceptible BALB/c mice, while the L. major sub-strain IR173 is highly controlled. These results suggest that factors other than IL-4 are capable of suppressing IFNgamma activated killing of intracellular L. major parasites. IL- 10 has been identified as the factor, which causes susceptibility to L. major LV39 in IL-4Ralpha-/- mice. In IL-4Ralpha-/- mice treated with neutralizing anti-IL-10 receptor antibody and in BALB/c mice genetically deficient for both IL-4Ralpha and IL-10, the disease to L. major LV39 infection was reversed to a healing phenotype. This proposal exploits the disparate outcomes of L. major LV39 and IR173 infections to assess cytokine regulation, the role of IL-10-secreting Treg cells, the roles of macrophages and dendritic cells in directing T cell immune responses to L. major infection, and the efficacy and mechanisms of protection by L. major vaccines. The long-term goal of these studies is to identify the cellular processes and antigens involved in L. major immune escape mechanisms, which are fully revealed in the absence of IL-4/IL- 13 signaling. These studies have implications for the development of therapies and vaccines directed toward Leishmania infections as well as the mechanisms that regulate Th1/Th2 cytokine development in vivo.